Effective strategies for promoting healthy brain aging and preventing Alzheimer's disease (AD) are increasingly important given the unprecedented growth of the elderly population and the resulting increase in the prevalence of AD. Evidence suggests that exercise and cardiorespiratory (CR) fitness may protect against cognitive decline and loss of gray matter density in normal aging. Little is known about CR fitness in individuals with early AD and whether fitness influences AD progression. Additionally, the mechanisms mediating a relationship between CR fitness and brain health are relatively unexplored. Potential biological mechanisms for how fitness may preserve brain health include reduced cerebrovascular disease in those with higher levels of physical activity and a possible disease-modifying effect of exercise on AD neuropathological burden, as demonstrated in mouse models of the disease. Our overall hypothesis is that CR fitness will be associated with reduced AD progression. To examine our hypotheses, we are longitudinally assessing the gold-standard measure of CR fitness, peak oxygen consumption, over two years in early-stage AD subjects (n = 75). Baseline evaluations on this cohort will be complete by the anticipated date of funding when two-year follow-up evaluations will begin. Aim 1 will examine the relationship between CR fitness (baseline and 2-year change) and clinical indicators of AD progression. In aim 2, we will longitudinally assess the relationship of CR fitness with hippocampal volume, a surrogate marker of AD pathological burden, to examine the relationship between CR fitness and AD neuropathological progression. In aim 3, we will assess the relationship between CR fitness and MRI-markers of vascular disease, including white matter lesion burden and infarcts. While aims 1 and 2 test specific hypotheses concerning the influence of fitness on AD, aim 3 is an embedded exploration of alternative mechanisms that may form the basis of an association between AD and fitness. A clear demonstration of the beneficial effects of fitness on brain aging and AD would be important for public health policy and effective for encouraging the 40-50 million adults in the US who do not currently obtain the recommended amount of physical activity. [unreadable] [unreadable] [unreadable]